Induction of subtle blood-brain barrier dysfunction using preclinical diagnostic ultrasound combined with microbubbles
Fluids and Barriers of the CNS, vol. 23
Abstract
BACKGROUND: The blood-brain barrier (BBB) plays a critical role in maintaining brain homeostasis by tightly regulating molecular transport. However, its integrity is often compromised with aging and in neurodegenerative diseases, contributing to disease pathology. Studying the biological consequences of BBB dysfunction independent of concomitant pathology remains challenging, largely due to the absence of reliable and inducible animal models that avoid unintended side effects such as osmotic effects, neuroinflammation, or vascular damage. In this study, we evaluated the use of Power Doppler ultrasound (PDUS) combined with microbubbles to induce widespread, bilateral BBB opening in the mouse brain. METHODS: Mice received intravenous infusions of SonoMAC microbubbles during transcranial PDUS application. BBB permeability was assessed via Evans Blue dye extravasation and immunofluorescence analysis of extravasated immunoglobulins. Vessel integrity was evaluated at the ultrastructural level using transmission electron microscopy (TEM). RESULTS: PDUS combined with microbubbles successfully induced widespread BBB opening, as evidenced by diffuse Evans Blue staining and immunoglobulin extravasation in coronal sections. Immunoglobulin leakage was detected in all analyzed brain regions, with lower levels in white matter, likely reflecting its lower vascular density. Leakage appeared to primarily originate from capillaries while TEM analysis revealed no overt vascular damage. CONCLUSIONS: These findings support PDUS with microbubbles as a non-destructive, reproducible method to model widespread BBB dysfunction. This approach offers an in vivo platform to study BBB-related pathophysiological processes such as impaired clearance, protein aggregation, and neurotoxicity, as well as for investigation of therapeutic delivery to the brain parenchyma.
Authors 9
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Shakira A. van der Panne corresponding
Amsterdam UMC Location University of Amsterdam · Amsterdam Neuroscience · Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences
Affiliation as printed
Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, The Netherlands. s.a.vanderpanne@amsterdamumc.nl
Amsterdam Neuroscience, Amsterdam University Medical Center, Amsterdam, The Netherlands. s.a.vanderpanne@amsterdamumc.nl
Department of Biomedical Engineering and Physics, Amsterdam University Medical Center, Amsterdam, The Netherlands. s.a.vanderpanne@amsterdamumc.nl
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers
Affiliation as printed
Department of Biomedical Engineering and Physics, Amsterdam University Medical Center, Amsterdam, The Netherlands
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Amsterdam University Medical Centers
Affiliation as printed
Electron Microscopy Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands
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Nicole N. van der Wel corresponding
Amsterdam University Medical Centers
Affiliation as printed
Electron Microscopy Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands
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University Medical Center Utrecht
Affiliation as printed
Center for Imaging Sciences, University Medical Center Utrecht, Utrecht, The Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers
Affiliation as printed
Amsterdam Neuroscience, Amsterdam University Medical Center, Amsterdam, The Netherlands
Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Amsterdam, The Netherlands
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Louise van der Weerd corresponding Aachen Department of Human Genetics Department of Radiology, Leiden University Medical Center
Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences
Affiliation as printed
Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, The Netherlands
Department of Biomedical Engineering and Physics, Amsterdam University Medical Center, Amsterdam, The Netherlands
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Amsterdam UMC Location University of Amsterdam · Amsterdam Neuroscience · Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences
Affiliation as printed
Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, The Netherlands
Amsterdam Neuroscience, Amsterdam University Medical Center, Amsterdam, The Netherlands
Department of Biomedical Engineering and Physics, Amsterdam University Medical Center, Amsterdam, The Netherlands
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